Methods of preventing the occurrence of cardiovascular events

ABSTRACT

The present invention relates to pharmacological interventions with pemafibrate for cardiovascular diseases and adverse cardiovascular events. In addition, the invention relates to the use of pemafibrate to treat dyslipidemia and type 2 diabetes mellitus and thereby reduce the risk of cardiovascular disease and adverse cardiovascular events.

PRIOR APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNos. 62/368,245 (filed Jul. 29, 2016) and 62/462,574 (filed Feb. 23,2017). The contents of these applications is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to pharmacological interventions withpemafibrate for cardiovascular diseases and adverse cardiovascularevents. In addition, the invention relates to the use of pemafibrate totreat dyslipidemia and type 2 diabetes mellitus and thereby reduce therisk of cardiovascular disease and adverse cardiovascular events.

BACKGROUND OF THE INVENTION

Cardiovascular diseases (CVDs) are a group of disorders of the heart andcirculatory system that include coronary heart disease, cerebrovasculardisease, peripheral arterial disease, rheumatic heart disease,congenital heart disease, deep vein thrombosis and pulmonary embolism.Despite significant advances in medical treatments, CVDs remain thenumber 1 cause of death globally. An estimated 17.5 million people diedfrom CVDs in 2012, representing 31% of all global deaths. Dyslipidemiais one of the primary risk factors for CVDs.

Dyslipidemia is an imbalance in a person's lipid metabolism, such thatone or more of the person's lipid values are associated with anincreased risk of CVDs. Dyslipidemia is particularly prevalent in type 2diabetes patients and other patients at high risk for CVDs. Dyslipidemiais typically characterized by one or a combination of elevated levels oflow-density lipoprotein cholesterol (LDL-C), elevated triglyceride (TG)levels, or low levels of high-density lipoprotein cholesterol (HDL-C),the so-called “good cholesterol.” Pharmacological therapies aimed attreating dyslipidemia are one of the principal tools employed byphysicians to reduce the risk of CVDs.

The Third Report of the National Cholesterol Education Program (NCEP)Expert Panel on Detection, Evaluation, and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel III) discloses cut-pointsfor initiating treatment for dyslipidemia, which can be used to evaluatecardiovascular risk. Under these standards, a person having an LDL-Cconcentration greater than 100 mg/dL (2.59 mmol/L) is at risk for acardiovascular event. A person having a total cholesterol concentrationgreater than 200 mg/dL (5.18 mmol/L) is at risk for a cardiovascularevent. A person having an HDL-C concentration less than 40 mg/dL (1.0mmol/L) for men and less than 50 mg/dL (1.3 mmol/L) for women is at riskfor a cardiovascular event. A person having a fasting triglycerideconcentration greater than 150 mg/dL (1.70 mmol/L) is at risk forcardiovascular events. A person having a non-HDL-C concentration greaterthan 130 mg/dL (3.37 mmol/L) is also at risk for a cardiovascular event.

Statins, also known as HMG-CoA reductase inhibitors, are one of thefirst classes of drugs approved by the United States Food and DrugAdministration for the treatment of dyslipidemia. This class of drugs isparticularly effective at reducing LDL-C levels in at-risk individuals,and has been credited with significantly decreasing the prevalence ofCVDs in the United States and around the world. However, statins aretypically less effective at modifying concentrations of other lipidsthat contribute to cardiovascular risk, such as elevated TGs, elevatedtotal cholesterol other than HDL (non-HDL-C), elevated apolipoproteinCIII (Apo CIII), elevated remnant cholesterol, and low HDL-C.

Other drug classes, particularly the fibrates, have also been developedto correct lipid imbalances. Fibrates activate peroxisomeproliferator-activated receptor alpha (PPARα) and are particularlyeffective at reducing extremely high levels of cholesterol ortriglycerides. As a consequence, fibrates are commonly used alone or incombination with other lipid-modifying therapies to treathypercholesterolemia and hypertriglyceridemia, although their utilityfor reducing the risk of CVDs has been called into question in severallarge randomized clinical trials. This is particularly true in patientsalready taking statins for their dyslipidemia, or type 2 diabetesmellitus patients.

The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes)(LANCET 2005; 366:1849-1861) and ACCORD (Action to ControlCardiovascular Risk in Diabetes) (N ENGL J MED 2010; 362:1563-1574)trials are frequently cited long-term placebo-controlled trialsevaluating the ability of fenofibrate to reduce cardiovascular risk inpatients with type 2 diabetes mellitus. The FIELD study enrolled 9795people aged 50-75 years with type 2 diabetes mellitus and not takingstatin therapy at study entry, and treated them for five years withplacebo or fenofibrate. Patients were eligible to participate in thetrial if they had a total-cholesterol concentration ranging from 3.0 to6.5 mmol/L; a total-cholesterol/HDL-cholesterol ratio of 4.0 or more;and serum triglycerides ranging from 1.0 to 5.0 mmol/L. The study didnot show a benefit in its primary endpoint of major coronary events,although secondary endpoints such as nonfatal myocardial infarction (MI)and coronary revascularization showed some potential benefit.

The ACCORD study investigated whether fenofibrate in combination with astatin, as compared with statin monotherapy, would reduce the risk ofcardiovascular disease in patients with type 2 diabetes mellitus(glycated hemoglobin level of 7.5% or more). Patients were eligible toparticipate in the trial if they had an LDL-C level of 60 to 180 mg perdeciliter (1.55 to 4.65 mmol per liter), an HDL-C level below 55 or 50mg per deciliter (1.42 or 1.29 mmol per liter), and a TG level below 750mg per deciliter (8.5 mmol per liter) if not receiving lipid therapy orbelow 400 mg per deciliter (4.5 mmol per liter) if receiving lipidtherapy. The primary outcome was the first occurrence of nonfatalmyocardial infarction, nonfatal stroke, or death from cardiovascularcauses. The mean follow-up was 4.7 years. The study did not detect asignificant treatment effect in its primary endpoint or in any of itssecondary endpoints.

Pemafibrate, whose chemical name is(2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoicacid, is a PPARα activator like fenofibrate, although it has proven muchmore potent at affecting lipid metabolism and is more specific for thePPARα receptor than fenofibrate. Thus, pemafibrate is also described asa selective PPARα modulator (SPPARMα). The drug is under development byKowa Company, Ltd. for the treatment of dyslipidemia and cardiovasculardisease.

A poster by Ishibashi et al. in EAS 2012 reports an evaluation of theefficacy of pemafibrate in comparison to placebo and fenofibrate inatherogenic dyslipidemia patients. The major inclusion criteria werefasting TG ≥200 mg/dL (2.26 mmol/L) and HDL-C ≤50 mg/dL (1.29 mmol/L)for males or ≤55 mg/dL (1.42 mmol/L) for females. The primary endpointswere percent change in fasting TG and the incidence of adverse events.The poster reports that while placebo increased fasting plasma TG levelsby 28.5%, pemafibrate reduced fasting plasma TG levels dose-dependentlyand by 42.7% with 0.2 mg BID, which was significantly lower than the29.7% reduction achieved by 100 mg/day of fenofibrate.

A poster by Araki et al. in EASD 2014 reports an integrated analysis oftwo Phase 2 trials (one pemafibrate monotherapy trial and one add-ontherapy to a stable 2 mg/day dose of pitavastatin) and one Phase 2/3trial (monotherapy). All subjects reportedly had hypertriglyceridemiaand low HDL-C and/or high non-HDL-C. The poster does not disclose actuallevels of TGs in the study population, or break out the results based onwhether the patient had low HDL-C or high non-HDL-C. The efficacy andsafety of pemafibrate 0.05, 0.1, 0.2 and 0.4 mg/day (twice daily) wereexamined in all trials. The poster reports a significant reduction in TGdose-dependently and an increase in HDL-C in all pemafibrate groups. Theposter also reports dose-dependent favorable effects on insulinsensitivity.

Despite these advances in lipid therapies, the clinical benefits offibrate-based lipid altering therapies remain unknown with largerandomized clinical trials yielding equivocal results. Pemafibrate is apromising drug, but it has not been shown to reduce cardiovascular risk.

Pharmacological therapies are needed that can alter lipid parameters ina beneficial way, particularly in patients with type 2 diabetes, orthose presenting with residual risk of cardiovascular events in spite ofstatin treatment, to lower the risk of adverse cardiovascular events.Better definitions of populations likely to benefit from such therapiesare also needed, based on lipid profiles and cardiovascular risk.

It is therefore an object of the present invention to providepemafibrate therapies that can reduce cardiovascular risk in patientswith one or more risk factors for cardiovascular events, particularly inpatients on concurrent statin treatment.

Another object of the present invention is to reduce cardiovascular riskin populations at risk for adverse cardiovascular events due to animbalanced lipid metabolism, particularly in patients with type 2diabetes mellitus.

Other objects of the present invention are to identify at-risk patientslikely to benefit from pemafibrate treatment and to define specificsubjects for such treatment.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to the surprising ability ofpemafibrate to reduce cardiovascular risk, in spite of equivocal resultsreported for known fibrates in the clinical literature. Thus, in a firstembodiment, the invention provides a method of preventing the occurrenceof cardiovascular events in a patient with one or more risk factors forcardiovascular diseases, comprising administering to the patient aneffective amount of pemafibrate or a pharmaceutically acceptable saltthereof.

In a second embodiment, the invention provides a method of treatingdyslipidemia in a patient with type 2 diabetes mellitus comprisingadministering to the patient a therapeutically effective amount ofpemafibrate or a pharmaceutically acceptable salt thereof, wherein thepatient has (a) a fasting TG concentration ≥175 mg/dL (2.26 mmol/L) and≤500 mg/dL (5.64 mmol/L); and (b) an HDL-C concentration 50 mg/dL ifmale or ≤55 mg/dL if female.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description serve to explain theinvention.

FIGS. 1A-1D report changes from baseline to Week 12 in TG [A], non-HDL-C[B], Apo CIII [C] and remnant-C [D] with pemafibrate versus placebo indyslipidemia patients receiving statin treatment, as described inExample 1. Each graph reports left to right 0.05 mg BID, 0.1 mg BID, 0.2mg BID, 0.1 mg QD, 0.2 mg QD, and 0.4 mg QD pemafibrate.

FIGS. 2A-2D report changes from baseline to Week 12 in TG [A], non-HDL-C[B], Apo CIII [C] and remnant-C [D] with pemafibrate versus placebo indyslipidemia patients with type 2 diabetes mellitus receiving statintreatment, as described in Example 2. Each graph reports left to right0.05 mg BID, 0.1 mg BID, 0.2 mg BID, 0.1 mg QD, 0.2 mg QD, and 0.4 mg QDpemafibrate.

FIGS. 3A-3D report changes from baseline to Week 12 in TG [A], VLDL-C,RemL-C, Apo CIII, non-HDL-C, LDL-C and Apo B [B], HDL-C, Apo AI and ApoAII [C], and fasting plasma glucose and HOMA-IR [D], with pemafibrateversus placebo in dyslipidemia patients receiving a stable dose ofpitavastatin, as reported in Example 3. Each graph reports left to rightplacebo, 0.1 mg BID, 0.2 mg BID, and 0.4 mg BID pemafibrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides the following:

-   1) A method of preventing the occurrence of cardiovascular events in    a patient with one or more risk factors, comprising administering to    the patient a therapeutically effective amount of pemafibrate or a    pharmaceutically acceptable salt thereof.-   2) The method according to 1), wherein the patient has type 2    diabetes mellitus.-   3) The method according to 1), wherein the patient has an age    greater than or equal to 50 years if male or 55 years if female, or    systemic atherosclerosis.-   4) The method according to 1), wherein the patient is taking    concurrent statins.-   5) The method according to 1), wherein the patient has a fasting TG    concentration ≥200 mg/dL and <500 mg/dL.-   6) The method according to 1), wherein the patient has an HDL-C    concentration ≤40 mg/dL.-   7) The method according to 1), wherein the patient has:    -   a) type 2 diabetes mellitus;    -   b) a fasting TG concentration ≥200 mg/dL and <500 mg/dL; and    -   c) an HDL-C concentration ≤40 mg/dL.-   8) The method according to 7) wherein:    -   a) the patient has an age greater than or equal to 50 years if        male or 55 years if female, or systemic atherosclerosis;    -   b) the therapeutically effective amount of pemafibrate or        pharmaceutically acceptable salt thereof is 0.4 mg, administered        orally per day; and    -   c) the cardiovascular events are selected from nonfatal        myocardial infarction, nonfatal ischemic stroke, hospitalization        for unstable angina requiring unplanned coronary        revascularization, cardiovascular death, or a combination        thereof.-   9) The method according to 1), wherein the patient is:    -   a) on concomitant moderate to high intensity statin therapy;    -   b) on concomitant lipid-lowering therapy other than the        concomitant moderate to high intensity statin therapy and has an        LDL-C concentration ≤70 mg/dL; or    -   c) statin-intolerant and has an LDL-C concentration ≤100 mg/dL.-   10) The method according to 1), wherein the therapeutically    effective amount of pemafibrate or pharmaceutically acceptable salt    thereof is from 0.2 to 1.0 mg, administered orally per day.-   11) The method according to 1), wherein the therapeutically    effective amount of pemafibrate or pharmaceutically acceptable salt    thereof is 0.4 mg, administered orally per day.-   12) The method according to 1), wherein the therapeutically    effective amount of pemafibrate or pharmaceutically acceptable salt    thereof is 0.2 mg, administered orally twice daily.-   13) The method according to 1), wherein the cardiovascular events    are selected from nonfatal myocardial infarction, nonfatal ischemic    stroke, hospitalization for unstable angina requiring unplanned    coronary revascularization, cardiovascular death, or a combination    thereof.-   14) The method according to 1), wherein the patient has type 2    diabetes mellitus as defined by:    -   a) a hemoglobin A1c level of 6.5% or greater; and    -   b) a plasma glucose level selected from:        -   i) greater than or equal to 126 mg/dL when fasting;        -   ii) greater than or equal to 200 mg/dL at 2 hours during            oral glucose tolerance testing; or        -   iii) greater than or equal to 200 mg/dL with classic type 2            diabetes mellitus symptoms.-   15) The method according to 1), wherein the patient has    cardiovascular disease.-   16) A method of treating dyslipidemia in a patient with type 2    diabetes mellitus comprising administering to the patient a    therapeutically effective amount of pemafibrate or a    pharmaceutically acceptable salt thereof, wherein the patient has:    -   a) a fasting TG concentration ≥175 mg/dL and ≤500 mg/dL; and    -   b) an HDL-C concentration ≤50 mg/dL if male or ≤55 mg/dL if        female.-   17) The method according to 16), wherein the patient has:    -   a) a fasting TG concentration ≥200 mg/dL and <500 mg/dL; and    -   b) an HDL-C concentration ≤40 mg/dL.-   18) The method according to 16), wherein the therapeutically    effective amount of pemafibrate or pharmaceutically acceptable salt    thereof is from 0.1 to 1.0 mg, administered orally per day.-   19) The method according to 16), wherein the therapeutically    effective amount of pemafibrate or pharmaceutically acceptable salt    thereof is 0.4 mg, administered orally per day.-   20) The method according to 16), wherein the therapeutically    effective amount of pemafibrate or pharmaceutically acceptable salt    thereof is 0.2 mg, administered orally twice daily.-   21) The method according to 16), wherein the patient has type 2    diabetes mellitus as defined by:    -   a) hemoglobin A1c level of 6.5% or greater; and    -   b) plasma glucose level is selected from:        -   i) greater than or equal to 126 mg/dL when fasting;        -   ii) greater than or equal to 200 mg/dL at 2 hours during            oral glucose tolerance testing; or        -   iii) greater than or equal to 200 mg/dL with classic type 2            diabetes mellitus symptoms.-   22) The method according to 16), wherein:    -   a) the patient has an age greater than or equal to 50 years if        male or 55 years if female, or systemic atherosclerosis;    -   b) the therapeutically effective amount of pemafibrate or        pharmaceutically acceptable salt thereof is 0.4 mg, administered        orally per day; and    -   c) the method is effective to prevent the occurrence of a        cardiovascular event selected from nonfatal myocardial        infarction, nonfatal ischemic stroke, hospitalization for        unstable angina requiring unplanned coronary revascularization,        cardiovascular death, or a combination thereof-   23) The method according to 16) or 17), wherein the patient has an    LDL-C concentration ≤100 mg/dL.-   24) The method according to 16) or 17), wherein the patient is:    -   a) on concomitant moderate to high intensity statin therapy;    -   b) on concomitant lipid-lowering therapy other than the        concomitant moderate to high intensity statin therapy and has an        LDL-C concentration ≤70 mg/dL; or    -   c) statin-intolerant and has an LDL-C concentration ≤100 mg/dL.-   25) The method according to 16), wherein the patient has    cardiovascular disease.-   26) A method of treating type 2 diabetes mellitus in a patient in    need thereof comprising administering to the patient a    therapeutically effective amount of pemafibrate or a    pharmaceutically acceptable salt thereof, wherein the patient has:    -   a) a fasting TG concentration ≥200 mg/dL and <500 mg/dL;    -   b) an HDL-C concentration ≤40 mg/dL; and    -   c) controlled LDL-C levels.-   27) A method of treating cardiovascular disease or preventing    adverse cardiovascular events in a patient with type 2 diabetes    mellitus, comprising administering to the patient a therapeutically    effective amount of pemafibrate or a pharmaceutically acceptable    salt thereof, wherein the patient has:    -   a) a fasting TG concentration ≥200 mg/dL and <500 mg/dL;    -   b) an HDL-C concentration ≤40 mg/dL; and    -   c) controlled LDL-C levels.-   28) The method according to 27) for preventing adverse    cardiovascular events wherein the cardiovascular event is selected    from nonfatal myocardial infarction, nonfatal ischemic stroke,    hospitalization for unstable angina requiring unplanned coronary    revascularization, cardiovascular death, or a combination thereof.-   29) A method of prolonging the time to first occurrence of:    -   a) any component of the primary endpoint in a subgroup of        subjects defined at baseline by: sex; presence or absence of        established CVD; and baseline lipid lowering therapy as defined        hierarchically by:        -   i) receiving treatment with a stable dose (i.e. for at least            12 weeks) of a qualifying moderate-to high intensity statin;            or        -   ii) statin intolerant and having evidence of LDL <100 mg/dl            (2.59 mmol/L) by a local laboratory determination within the            previous 12 months; or        -   iii) having evidence of LDL-C <70 mg/dl (1.81 mmol/L) by a            local laboratory determination within the previous 12 months            if untreated or on stable dosing (i.e. for at least 12            weeks) of another lipid-lowering regimen including a PCSK9            inhibitor.    -   b) any component of nonfatal MI, nonfatal ischemic stroke,        hospitalization of for unstable angina requiring unplanned        coronary revascularization, CV death, or any coronary        revascularization;    -   c) any component of nonfatal MI, nonfatal ischemic stroke,        hospitalization for unstable angina requiring unplanned coronary        revascularization, or all-cause mortality;    -   d) any component of nonfatal MI, nonfatal ischemic stroke, CV        death, any coronary revascularization, or hospitalization for        heart failure;    -   e) any component of nonfatal MI, nonfatal stroke (any), CV        death, or hospitalization for unstable angina requiring        unplanned coronary revascularization;    -   f) individual components of the primary endpoint, nonfatal        stroke (any), all cause mortality, and hospitalization for heart        failure;    -   g) diabetic retinopathy, as assessed by use of retinal laser        treatment, anti-vascular endothelial growth factor therapy, or        vitrectomy due to development of and/or deterioration in        diabetic retinopathy;    -   h) diabetic nephropathy, as assessed by an increase in        microalbumin/creatinine ratio to >30 mg/g among those without        microalbuminuria at baseline, and categorical change from        baseline albuminuria (normo-, micro-, or macroalbuminuria),        doubling of creatinine from baseline, creatinine level >6.0        mg/dl, glomerular filtration rate (GFR) <15 ml/ml, or initiation        of renal replacement therapy (dialysis or transplant), among all        subjects; and    -   i) peripheral artery disease, defined as incidence of        lower-extremity revascularization, intermittent claudication,        rest pain, lower-extremity ischemic ulceration, or amputation        with either ankle brachial index ≤0.9 or other diagnostic        testing (e.g., angiogram, toe-brachial index, or imaging study),    -   wherein the method comprises administering to a subject in need        thereof a therapeutically effective amount of pemafibrate or a        pharmaceutically acceptable salt thereof.-   30) A method of prolonging the time to first occurrence of:    -   a) any component of the 3-component composite endpoint of        non-fatal MI, non-fatal stroke, or cardiovascular death;    -   b) any component of the primary endpoint or hospitalization for        heart failure;    -   c) any component of the primary endpoint or all-cause mortality;    -   d) any component of the primary endpoint, any coronary        revascularization, or hospitalization for heart failure; or    -   e) any new or worsening peripheral artery disease, defined as        incidence of lower extremity revascularization, intermittent        claudication, rest pain, lower extremity ischemic ulceration, or        major amputation with either ankle-brachial index ≤0.9 or other        diagnostic testing (eg, toe-brachial index, angiogram, or other        imaging study).-   31) The method according to 3), wherein systemic atherosclerosis is    defined by:    -   a) prior myocardial infarction or ischemic (non-hemorrhagic)        stroke;    -   b) coronary angiographic lesion of ≥60% stenosis in a major        epicardial vessel or ≥50% left main stenosis;    -   c) asymptomatic carotid disease with ≥70% carotid artery        stenosis;    -   d) symptomatic carotid disease with ≥50% carotid artery        stenosis;    -   e) symptomatic lower extremity peripheral artery disease        selected from intermittent claudication, rest pain, or lower        extremity ischemic ulceration with an ankle-brachial index ≤0.9;        or    -   f) prior arterial revascularization procedure selected from        coronary, carotid or peripheral angioplast, stenting, bypass,        atherectomy, or endarterectomy.-   32) The method according to 1), wherein the patient does not have    systemic atherosclerosis.

As used in the specification and claims, the singular forms “a,” “an,”and “the” include plural references unless the context clearly dictatesotherwise. For example, the term “a pharmaceutical excipient” refers toone or more pharmaceutical excipients for use in the presently disclosedformulations and methods.

The use of numerical values in the various quantitative values specifiedin this application, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about”. Also, thedisclosure of ranges is intended as a continuous range including everyvalue between the minimum and maximum values recited as well as anyranges that can be formed by such values. Also disclosed herein are anyand all ratios (and ranges of any such ratios) that can be formed bydividing a disclosed numeric value into any other disclosed numericvalue. Accordingly, the skilled person will appreciate that many suchratios, ranges, and ranges of ratios can be unambiguously derived fromthe numerical values presented herein and in all instances such ratios,ranges, and ranges of ratios represent various embodiments of thepresent invention.

As used herein, “cardiovascular events” includes cardiovascular death;nonfatal myocardial infarction; nonfatal ischemic stroke; unstableangina (e.g., unstable angina determined to be caused by myocardialischemia by, for example, invasive or non-invasive testing, andrequiring hospitalization); cardiac arrest; peripheral cardiovasculardisease requiring intervention, angioplasty, bypass surgery or aneurysmrepair; and onset of new congestive heart failure.

As used herein, “preventing the occurrence of cardiovascular events”includes delaying the incidence of cardiovascular events as well asminimizing the severity of cardiovascular events. It also refers a timeinterval beginning at (a) an initial administration of a therapeuticallyeffective amount of pemafibrate or a pharmaceutically acceptable saltthereof as disclosed herein to the patient to (b) a cardiovascular eventin the patient greater than or substantially greater than a control timeinterval beginning at (a′) initial administration of a placebo tocontrol subjects to (b′) a cardiovascular event in the control subjects.In some embodiments, the cardiovascular event of the patient is selectedfrom those noted above. In some embodiments, the cardiovascular event ofthe control subjects is selected from those noted above.

As used herein, “therapeutically effective amount” refers to an amountsufficient to elicit the desired biological response in a patient. Thetherapeutically effective amount or dose depends on the age, sex andweight of the patient, and the current medical condition of the patient.The skilled artisan can determine appropriate amount or dose dependingon the above factors based on his or her knowledge and the teachingscontained herein.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.“Pharmaceutically acceptable salts” means salts that arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity.

The terms “treating” and “treatment,” when used herein, refer to themedical management of a patient with the intent to cure, ameliorate,stabilize, or prevent a disease, pathological condition, or disorder(collectively “disorder”). These terms include active treatment, thatis, treatment directed specifically toward the improvement of adisorder, and also include causal treatment, that is, treatment directedtoward removal of the cause of the associated disorder. In addition,this term includes palliative treatment, that is, treatment designed forthe relief of symptoms rather than the curing of the disorder;preventative treatment, that is, treatment directed to minimizing orpartially or completely inhibiting or delaying the development of thedisorder; and supportive treatment, that is, treatment employed tosupplement another specific therapy directed toward the improvement ofthe disorder.

“Treatment of dyslipidemia” includes the correction of one or more lipidimbalances in the human body, even if the concentration of other lipidsremains in an unhealthy state.

All analyte measurements recited herein, when used to define a patientdescribed herein, are measured at the beginning of pemafibratetreatment.

Unless stated herein to the contrary, all analyte measurements are takenin the fasting state, and are based on the concentration of the analytein plasma or serum. The fasting state means that the patient has noteaten anything in from 8 to 12 hours, except for water. Standard methodsof measuring analytes can be found in Lab Protocols for NHANES 2003-2004data published by the United States Centers for Disease Control.

Unless stated herein to the contrary, all methods described herein areperformed in all ages, preferably adults, more preferably greater than50 years if male and greater than 55 years if female.

As used herein, the term “significantly” refers to a level ofstatistical significance. The level of statistical significant can be,for example, of at least p<0.05, of at least p<0.01, of at leastp<0.005, or of at least p<0.001.

Statins, also known as HMG-CoA reductase inhibitors, includeatorvastatin, simvastatin, fluvastatin, pitavastatin, rosuvastatin,pravastatin, and lovastatin and their pharmaceutically acceptable salts.

Dyslipidemia is an elevation of plasma cholesterol, triglycerides (TGs),or both, or a low high-density lipoprotein level that contributes to thedevelopment of atherosclerosis. Causes may be primary (genetic) orsecondary. Diagnosis is performed by measuring plasma levels of totalcholesterol, TGs, and individual lipoproteins. Treatment involvesdietary changes, exercise, and lipid-lowering drugs.

In a first embodiment, the invention provides a method of preventing theoccurrence of cardiovascular events in a patient with one or more riskfactors, comprising administering to the patient an effective amount ofpemafibrate or a pharmaceutically acceptable salt thereof.

In a preferred first embodiment, the invention provides a method ofpreventing the occurrence of cardiovascular events in a patient with oneor more of multiple risk factors, comprising administering to thepatient an effective amount of pemafibrate or a pharmaceuticallyacceptable salt thereof.

According to this embodiment, the occurrence of cardiovascular eventscan be prevented. That is, the occurrence of the following events can beprevented: cardiovascular death; nonfatal myocardial infarction;nonfatal ischemic stroke; coronary revascularization; unstable angina(e.g., unstable angina determined to be caused by myocardial ischemiaby, for example, invasive or non-invasive testing, and requiringhospitalization); cardiac arrest; peripheral cardiovascular diseaserequiring intervention, angioplasty, bypass surgery or aneurysm repair;and onset of new congestive heart failure.

In a preferred first embodiment, the occurrence of: (a) nonfatalmyocardial infarction, (b) nonfatal ischemic stroke, (c) hospitalizationfor unstable angina requiring unplanned coronary revascularization, (d)cardiovascular death; or a combination thereof can be prevented.

In another preferred first embodiment, the risk of a cardiovascularevent, for example (a) nonfatal myocardial infarction, (b) nonfatalischemic stroke, (c) hospitalization for unstable angina requiringunplanned coronary revascularization, (d) cardiovascular death; or acombination thereof can be reduced.

In another preferred first embodiment, the method can be performed inpatients along with statin treatment, or who have controlled LDL-Clevels (i.e. LDL-C levels less than or equal to 70 or 100 mg/dL). If thepatient is on concomitant moderate to high intensity statin therapy, itcan be assumed that the patient has low or controlled LDL-C levels. Inthis embodiment, statins can be selected from rosuvastatin,pitavastatin, atorvastatin, fluvastatin, simvastatin, pravastatin andlovastatin, preferably selected from atorvastatin ≥40 mg/d, rosuvastatin≥20 mg/d, simvastatin ≥40 mg/d, or pitavastatin 4 mg/d. In addition, ifthe patient is on concomitant lipid-lowering therapy, the patient can bepresumed to have low or controlled LDC levels if the patient has a LDL-Cconcentration less than or equal to 70 mg/dL. If the patient isstatin-intolerant, the patient can be presumed to have low or controlledLDL levels if the patient has a LDL-C concentration less than or equalto 100 mg/dL. In this embodiment, “lipid-lowering therapy” includestherapy in which the patient is treated by a lipid-lowering drug such asa statin e.g. rosuvastatin, pitavastatin, atorvastatin, fluvastatin,simvastatin, pravastatin and lovastatin; an inhibitor of cholesterolabsorption in the small intestine e.g. ezetimibe; probucol; niacin; bileacid sequestrants, e.g. cholestyramine; omega-3 fatty acids, e.g.eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Thus, in one preferred first embodiment the method is performed inpatients: a) on concomitant moderate to high intensity statin therapy;b) on concomitant lipid-lowering therapy other than the concomitantmoderate to high intensity statin therapy and having an LDL-Cconcentration ≤70 mg/dL; or c) who are statin-intolerant and have anLDL-C concentration ≤100 mg/dL.

This first embodiment is preferably practiced in patients with one ormore risk factors for cardiovascular events selected from: (i) elevatedfasting triglyceride levels; (ii) low HDL-C; (iii) type 2 diabetesmellitus; (iv) age (male ≥50 or female ≥55); (v) atherosclerosis; (vi)hypertension; (vii) smoking; and (viii) family history of early coronaryheart disease. It is known that a habit of smoking and/or a familyhistory of early coronary heart disease raise the risk forcardiovascular events. As used herein, the risk factors forcardiovascular disease are also referred as “multiple risk factors”.

Elevated fasting triglyceride levels refers to a fasting triglyceridelevel greater than 150, 160, 170, 175, 180, 190, 200, or 210 mg/dLtriglycerides, with 200 mg/dL (2.26 mmol/L) defining a preferred cutoffvalue. The upper limit of the patient's fasting triglyceride is notparticularly limited, but less than 500 mg/dL is a preferred cutoffvalue.

Low HDL-C levels refers to an HDL-C level at which the patient is atrisk for a cardiovascular event, and can be different depending on thepatient's sex. In preferred embodiments, the patient can be said to havea low HDL-C level if the patient has an HDL-C concentration less than55, 50, 45, 40 or 35 mg/dL, preferably ≤50 mg/dL if male or ≤55 mg/dL iffemale. More preferably, 40 mg/dL (1.034 mmol/L) HDL-C will define thecutoff value.

Other lipid values and their cutoff values can also be used to definethe patients treated by this first embodiment, including elevatednon-HDL-C, elevated Apo CIII, and elevated remnant cholesterol. In oneembodiment, the patient's non-HDL-C concentration is greater than 130,160, or 190 mg/dL. In another embodiment, the patient's remnantcholesterol level is greater than 5.0, 5.3, 5.6, or 5.9 mg/dL. In yetanother embodiment, the patient's Apo CIII concentration is 5 to 20mg/dL, for example, 5.8 to 10 mg/dL for male and 5.4 to 9.0 mg/dL forfemale.

In another preferred first embodiment, the patient being treated hastype 2 diabetes mellitus, defined as a patient with: elevated glycatedhemoglobin A1c levels and elevated plasma glucose levels. A patienthaving a glycated hemoglobin A1c concentration of 6.5% (48 mmol/mol) orgreater, on two consecutive tests may typically be considered to havetype 2 diabetes mellitus, particularly when combined with an elevatedplasma glucose level. An elevated plasma glucose level can be defined byone of three tests: (i) greater than or equal to 126 mg/dL (7.0 mmol/L)fasting plasma glucose level; (ii) greater than or equal to 200 mg/dL(11.1 mmol/L) plasma glucose level at 2 hours during oral glucosetolerance testing; (iii) a random plasma glucose level greater than orequal to 200 mg/dL with classic type 2 diabetes mellitus symptoms (i.e.frequent urination and extreme thirst); or (iv) currently takingmedication for treatment of diabetes. For oral glucose tolerancetesting, the patient fasts overnight, and fasting blood sugar level ismeasured. The patient then drinks a sugary liquid, and blood sugarlevels are tested periodically for the next two hours.

Insulin resistance, as measured by HOMA-IR (homeostasis modelassessment-estimated insulin resistance), may also be used to diagnosetype 2 diabetes mellitus. As used herein, HOMA-IR refers to theHomeostasis Model Assessment for Insulin Resistance or “insulinresistance score,” as reported by Matthews et al. Diabetologia 1985;28:412-419. HOMA-IR can be computed with the formula: fasting plasmaglucose (mmol/l) times fasting serum insulin (mU/l) divided by 22.5. LowHOMA-IR values indicate high insulin sensitivity, whereas high HOMA-IRvalues indicate low insulin sensitivity (i.e. insulin resistance).

Age is known as one of the multiple risk factors for cardiovasculardisease, especially greater than 50 years of age if male and greaterthan 55 years of age if female.

A patient with atherosclerosis includes any patient with (i) priormyocardial infarction or ischemic (non-hemorrhagic) stroke; (ii)coronary angiographic lesion of ≥60% stenosis in a major epicardialvessel or ≥50% left main stenosis; (iii) asymptomatic carotid diseasewith ≥70% carotid artery stenosis; (iv) symptomatic carotid disease with≥50% carotid artery stenosis; (v) symptomatic lower extremity peripheralartery disease selected from intermittent claudication, rest pain, lowerextremity ischemic ulceration, or major amputation with anankle-brachial index ≤0.9 or other diagnostic testing (e.g, toe-brachialindex, angiogram, or other imaging study); (vi) prior arterialrevascularization procedure selected from coronary, carotid orperipheral angioplasty, stenting, bypass, atherectomy, orendarterectomy; or (vii) a combination thereof.

Hypertension can be defined as having a systolic blood pressure ofgreater than 120, 130, 140, or 160 mmHg and a diastolic blood pressuregreater than 80, 90, or 100 mmHg.

The therapeutically effective amount of pemafibrate can be defined as arange of suitable doses on a daily basis. Thus, in one embodiment, thetherapeutically effective amount is from 0.1 to 1.0 mg of pemafibrate ora pharmaceutically acceptable salt thereof, administered orally per day.In another embodiment the therapeutically effective amount is from 0.2to 0.8 mg of pemafibrate or a pharmaceutically acceptable salt thereof,administered orally per day. In still another embodiment thetherapeutically effective amount is 0.4 mg of pemafibrate or apharmaceutically acceptable salt thereof, administered orally per day.These doses are preferably based on the weight of the free base ofpemafibrate.

In a second embodiment, the invention provides a method of treatingdyslipidemia in a patient with type 2 diabetes mellitus comprisingadministering to the patient a therapeutically effective amount ofpemafibrate or a pharmaceutically acceptable salt thereof for atherapeutically effective period of time, wherein the patient has (a) anelevated fasting triglyceride level; (b) a low HDL-C concentration; and(c) controlled LDL-C levels.

In this second embodiment, elevated fasting triglyceride levelspreferably refers to a fasting triglyceride level greater than 150, 160,170, 175, 180, 190, 200, or 210 mg/dL triglycerides, with 175 or 200mg/dL defining a particularly preferred cutoff value. The upper limit ofthe patient's fasting triglyceride levels is not particularly limited,but a cutoff value not greater than 500 mg/dL is preferred.

In this second embodiment, a low HDL-C level preferably refers to anHDL-C level at which the patient is at risk for an adversecardiovascular event, and can be different depending on the patient'ssex. In preferred embodiments the patient can be said to have a lowHDL-C level if the patient has an HDL-C concentration less than 55, 50,45, 40 or 35 mg/dL. A preferred cutoff value is ≤50 mg/dL if male or ≤55mg/dL if female. A particularly preferred cutoff value is ≤40 mg/dLwithout regard to sex.

In this second embodiment, a patient with controlled LDL-C levels canrefer to a patient having an LDL-C concentration ≤100 or 70 mg/dL, butpreferably refers to a patient who is on concurrent statin therapy. Aparticularly preferred patient is: a) on concomitant moderate to highintensity statin therapy; b) on concomitant lipid-lowering therapy otherthan the concomitant moderate to high intensity statin therapy and hasan LDL-C concentration ≤70 mg/dL; or c) statin-intolerant and has LDL-Cconcentration ≤100 mg/dL.

In this second embodiment, a patient with type 2 diabetes mellitus canbe defined as a patient with: elevated glycated hemoglobin A1c levelsand elevated plasma glucose levels. A patient having a glycatedhemoglobin A1c concentration of 6.5% (48 mmol/mol) or greater, on twoconsecutive tests may typically be considered to have type 2 diabetesmellitus, particularly when combined with an elevated plasma glucoselevel. The elevated plasma glucose level can be defined by one of threetests: (i) greater than or equal to 126 mg/dL (7.0 mmol/L) fastingplasma glucose level; (ii) greater than or equal to 200 mg/dL (11.1mmol/L) plasma glucose level at 2 hours during oral glucose tolerancetesting; (iii) a random plasma glucose level greater than or equal to200 mg/dL with classic type 2 diabetes mellitus symptoms; or (iv)currently taking medication for treatment of diabetes.

The therapeutically effective amount of pemafibrate for this secondembodiment can be defined as a range of suitable doses on a daily basis.Thus, in one embodiment, the therapeutically effective amount is from0.1 to 1.0 mg of pemafibrate or a pharmaceutically acceptable saltthereof, administered orally per day. In another embodiment thetherapeutically effective amount is from 0.2 to 0.8 mg of pemafibrate ora pharmaceutically acceptable salt thereof, administered orally per day.In still another embodiment the therapeutically effective amount is 0.4mg of pemafibrate or a pharmaceutically acceptable salt thereof,administered orally per day. These doses are preferably based on theweight of the free base of pemafibrate.

Other lipid values and their cutoff values can also be used to definethe patients treated by this second embodiment, including elevatednon-HDL-C, elevated Apo CIII, and elevated remnant cholesterol. In oneembodiment, the patient's non-HDL-C concentration is greater than 130,160, or 190 mg/dL. In another embodiment, the patient's remnantcholesterol level is greater than 5.0, 5.3, 5.6, or 5.9 mg/dL. In yetanother embodiment, the patient's Apo CIII concentration is 5 to 20mg/dL, for example, 5.8 to 10 mg/dL for male and 5.4 to 9.0 mg/dL forfemale.

Thus, in this second embodiment, the invention preferably provides amethod of treating dyslipidemia in a patient with type 2 diabetesmellitus comprising administering to the patient a therapeuticallyeffective amount of pemafibrate or a pharmaceutically acceptable saltthereof for a therapeutically effective period of time, wherein thepatient has (a) a fasting TG concentration 175 mg/dL (2.26 mmol/L) and<500 mg/dL (5.64 mmol/L); (b) a HDL-C concentration 50 mg/dL if a maleand 55 mg/dL if a female; and controlled LDL-C levels.

In this second embodiment, the invention most preferably provides amethod of treating dyslipidemia in a patient with type 2 diabetesmellitus comprising administering to the patient a therapeuticallyeffective amount of pemafibrate or a pharmaceutically acceptable saltthereof for a therapeutically effective period of time, wherein thepatient has (a) a fasting TG concentration ≥200 mg/dL (2.26 mmol/L) and<500 mg/dL (5.64 mmol/L); (b) an HDL-C concentration ≤40 mg/dL (1.034mmol/L); and LDL-C levels ≤100 mg/dL.

In a third embodiment, the invention provides a method of treating type2 diabetes mellitus in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount ofpemafibrate or a pharmaceutically acceptable salt thereof for atherapeutically effective period of time, wherein the patient has (a) anelevated fasting triglyceride level; (b) a low HDL-C concentration; and(c) controlled LDL-C levels.

In this third embodiment, elevated fasting triglyceride levelspreferably refers to a fasting triglyceride level greater than 150, 160,170, 175, 180, 190, 200, or 210 mg/dL triglycerides, with 175 or 200mg/dL defining a particularly preferred cutoff value. The upper limit ofthe patient's fasting triglyceride levels is not particularly limited,but a cutoff value not greater than 500 mg/dL is preferred.

In this third embodiment, a low HDL-C level preferably refers to anHDL-C level at which the patient is at risk for an adversecardiovascular event, and can be different depending on the patient'ssex. In preferred embodiments the patient can be said to have a lowHDL-C level if the patient has an HDL-C concentration less than 55, 50,45, 40 or 35 mg/dL. A preferred cutoff value is ≤50 mg/dL if male or ≤55mg/dL if female. A particularly preferred cutoff value is ≤40 mg/dLwithout regard to sex.

In this third embodiment, a patient with controlled LDL-C levels canrefer to a patient having an LDL-C concentration ≤100 or 70 mg/dL, butpreferably refers to a patient who is on concurrent statin therapy. Aparticularly preferred patient is: a) on concomitant moderate to highintensity statin therapy; b) on concomitant lipid-lowering therapy otherthan the concomitant moderate to high intensity statin therapy and hasan LDL-C concentration ≤70 mg/dL; or c) statin-intolerant and has LDL-Cconcentration ≤100 mg/dL.

In this third embodiment, a patient with type 2 diabetes mellitus can bedefined as a patient with: elevated glycated hemoglobin A1c levels andelevated plasma glucose levels. A patient having a glycated hemoglobinA1c concentration of 6.5% (48 mmol/mol) or greater, on two consecutivetests may typically be considered to have type 2 diabetes mellitus,particularly when combined with an elevated plasma glucose level. Theelevated plasma glucose level can be defined by one of three tests: (i)greater than or equal to 126 mg/dL (7.0 mmol/L) fasting plasma glucoselevel; (ii) greater than or equal to 200 mg/dL (11.1 mmol/L) plasmaglucose level at 2 hours during oral glucose tolerance testing; (iii) arandom plasma glucose level greater than or equal to 200 mg/dL withclassic type 2 diabetes mellitus symptoms; or (iv) currently takingmedication for treatment of diabetes.

The therapeutically effective amount of pemafibrate for this thirdembodiment can be defined as a range of suitable doses on a daily basis.Thus, in one embodiment, the therapeutically effective amount is from0.1 to 1.0 mg of pemafibrate or a pharmaceutically acceptable saltthereof, administered orally per day. In another embodiment thetherapeutically effective amount is from 0.2 to 0.8 mg of pemafibrate ora pharmaceutically acceptable salt thereof, administered orally per day.In still another embodiment the therapeutically effective amount is 0.4mg of pemafibrate or a pharmaceutically acceptable salt thereof,administered orally per day. These doses are preferably based on theweight of the free base of pemafibrate.

Other lipid values and their cutoff values can also be used to definethe patients treated by this third embodiment, including elevatednon-HDL-C, elevated Apo CIII, and elevated remnant cholesterol. In oneembodiment, the patient's non-HDL-C concentration is greater than 130,160, or 190 mg/dL. In another embodiment, the patient's remnantcholesterol level is greater than 5.0, 5.3, 5.6, or 5.9 mg/dL. In yetanother embodiment, the patient's Apo CIII concentration is 5 to 20mg/dL, for example, 5.8 to 10 mg/dL for male and 5.4 to 9.0 mg/dL forfemale.

Thus, in this third embodiment, the invention preferably provides amethod of treating dyslipidemia in a patient with type 2 diabetesmellitus comprising administering to the patient a therapeuticallyeffective amount of pemafibrate or a pharmaceutically acceptable saltthereof for a therapeutically effective period of time, wherein thepatient has (a) a fasting TG concentration ≥175 mg/dL (2.26 mmol/L) and<500 mg/dL (5.64 mmol/L); (b) a HDL-C concentration ≤50 mg/dL if a maleand ≤55 mg/dL if a female; and controlled LDL-C levels.

In this third embodiment, the invention most preferably provides amethod of treating dyslipidemia in a patient with type 2 diabetesmellitus comprising administering to the patient a therapeuticallyeffective amount of pemafibrate or a pharmaceutically acceptable saltthereof for a therapeutically effective period of time, wherein thepatient has (a) a fasting TG concentration ≥200 mg/dL (2.26 mmol/L) and<500 mg/dL (5.64 mmol/L); (b) a HDL-C concentration ≤40 mg/dL (1.034mmol/L); and LDL-C levels ≤100 mg/dL.

In a fourth embodiment, the invention provides a method of treatingcardiovascular disease or preventing cardiovascular events in a patientwith type 2 diabetes mellitus comprising administering to the patient atherapeutically effective amount of pemafibrate or a pharmaceuticallyacceptable salt thereof for a therapeutically effective period of time,wherein the patient has (a) an elevated fasting triglyceride level; (b)a low HDL-C concentration; and (c) controlled LDL-C levels.

In this fourth embodiment, elevated fasting triglyceride levelspreferably refers to a fasting triglyceride level greater than 150, 160,170, 175, 180, 190, 200, or 210 mg/dL triglycerides, with 175 or 200mg/dL defining a particularly preferred cutoff value. The upper limit ofthe patient's fasting triglyceride levels is not particularly limited,but a cutoff value not greater than 500 mg/dL is preferred.

In this fourth embodiment, a low HDL-C level preferably refers to anHDL-C level at which the patient is at risk for an adversecardiovascular event, and can be different depending on the patient'ssex. In preferred embodiments the patient can be said to have a lowHDL-C level if the patient has an HDL-C concentration less than 55, 50,45, 40 or 35 mg/dL. A preferred cutoff value is ≤50 mg/dL if male or ≤55mg/dL if female. A particularly preferred cutoff value is ≤40 mg/dLwithout regard to sex.

In this fourth embodiment, a patient with controlled LDL-C levels canrefer to a patient having an LDL-C concentration ≤100 or 70 mg/dL, butpreferably refers to a patient who is on concurrent statin therapy. Aparticularly preferred patient is: a) on concomitant moderate to highintensity statin therapy; b) on concomitant lipid-lowering therapy otherthan the concomitant moderate to high intensity statin therapy and hasan LDL-C concentration ≤70 mg/dL; or c) statin-intolerant and has LDL-Cconcentration ≤100 mg/dL.

In this fourth embodiment, a patient with type 2 diabetes mellitus canbe defined as a patient with: elevated glycated hemoglobin A1c levelsand elevated plasma glucose levels. A patient having a glycatedhemoglobin A1c concentration of 6.5% (48 mmol/mol) or greater, on twoconsecutive tests may typically be considered to have type 2 diabetesmellitus, particularly when combined with an elevated plasma glucoselevel. The elevated plasma glucose level can be defined by one of threetests: (i) greater than or equal to 126 mg/dL (7.0 mmol/L) fastingplasma glucose level; (ii) greater than or equal to 200 mg/dL (11.1mmol/L) plasma glucose level at 2 hours during oral glucose tolerancetesting; (iii) a random plasma glucose level greater than or equal to200 mg/dL with classic type 2 diabetes mellitus symptoms; or (iv)currently taking medication for treatment of diabetes.

The therapeutically effective amount of pemafibrate for this fourthembodiment can be defined as a range of suitable doses on a daily basis.Thus, in one embodiment, the therapeutically effective amount is from0.1 to 1.0 mg of pemafibrate or a pharmaceutically acceptable saltthereof, administered orally per day. In another embodiment thetherapeutically effective amount is from 0.2 to 0.8 mg of pemafibrate ora pharmaceutically acceptable salt thereof, administered orally per day.In still another embodiment the therapeutically effective amount is 0.4mg of pemafibrate or a pharmaceutically acceptable salt thereof,administered orally per day. These doses are preferably based on theweight of the free base of pemafibrate.

Other lipid values and their cutoff values can also be used to definethe patients treated by this fourth embodiment, including elevatednon-HDL-C, elevated Apo CIII, and elevated remnant cholesterol. In oneembodiment, the patient's non-HDL-C concentration is greater than 130,160, or 190 mg/dL. In another embodiment, the patient's remnantcholesterol level is greater than 5.0, 5.3, 5.6, or 5.9 mg/dL. In yetanother embodiment, the patient's Apo CIII concentration is 5 to 20mg/dL, for example, 5.8 to 10 mg/dL for male and 5.4 to 9.0 mg/dL forfemale.

Thus, in this fourth embodiment, the invention preferably provides amethod of treating dyslipidemia in a patient with type 2 diabetesmellitus comprising administering to the patient a therapeuticallyeffective amount of pemafibrate or a pharmaceutically acceptable saltthereof for a therapeutically effective period of time, wherein thepatient has (a) a fasting TG concentration ≥175 mg/dL (2.26 mmol/L) and<500 mg/dL (5.64 mmol/L); (b) a HDL-C concentration ≤50 mg/dL if a maleand ≤55 mg/dL if a female; and controlled LDL-C levels.

In this fourth embodiment, the invention most preferably provides amethod of treating dyslipidemia in a patient with type 2 diabetesmellitus comprising administering to the patient a therapeuticallyeffective amount of pemafibrate or a pharmaceutically acceptable saltthereof for a therapeutically effective period of time, wherein thepatient has (a) a fasting TG concentration ≥200 mg/dL (2.26 mmol/L) and<500 mg/dL (5.64 mmol/L); (b) a HDL-C concentration ≤40 mg/dL (1.034mmol/L); and LDL-C levels ≤100 mg/dL.

In a fifth embodiment, the invention provides a method of prolonging thetime to first occurrence of:

a) any component of the primary endpoint in subgroups of subjectsdefined at baseline by: sex; presence or absence of established CVD; andbaseline lipid lowering therapy as defined hierarchically by:

-   -   i) receiving treatment with a stable dose (i.e. for at least 12        weeks) of a qualifying moderate-to high intensity statin; or    -   ii) statin intolerant and have evidence of LDL <100 mg/dl (2.59        mmol/L) by local laboratory determination within the previous 12        months; or    -   iii) have evidence of LDL-C <70 mg/dl (1.81 mmol/L) by local        laboratory determination within the previous 12 months if        untreated or on stable dosing (i.e. for at least 12 weeks) of        another lipid-lowering regimen including a PCSK9 inhibitor.

b) any component of nonfatal MI, nonfatal ischemic stroke,hospitalization of for unstable angina requiring unplanned coronaryrevascularization, CV death, or any coronary revascularization;

c) any component of nonfatal MI, nonfatal ischemic stroke,hospitalization for unstable angina requiring unplanned coronaryrevascularization, or all-cause mortality;

d) any component of nonfatal MI, nonfatal ischemic stroke, CV death, anycoronary revascularization, or hospitalization for heart failure;

e) any component of nonfatal MI, nonfatal stroke (any), CV death, orhospitalization for unstable angina requiring unplanned coronaryrevascularization;

f) individual components of the primary endpoint, nonfatal stroke (any),all cause mortality, and hospitalization for heart failure;

g) diabetic retinopathy, as assessed by use of retinal laser treatment,anti-vascular endothelial growth factor therapy, or vitrectomy due todevelopment of and/or deterioration in diabetic retinopathy;

h) diabetic nephropathy, as assessed by an increase inmicroalbumin/creatinine ratio to >30 mg/g among those withoutmicroalbuminuria at baseline, and categorical change from baselinealbuminuria (normo-, micro-, or macroalbuminuria), doubling ofcreatinine from baseline, creatinine level >6.0 mg/dl, glomerularfiltration rate (GFR) <15 ml/ml, or initiation of renal replacementtherapy (dialysis or transplant), among all subjects; and

i) peripheral artery disease, defined as incidence of lower-extremityrevascularization, intermittent claudication, rest pain, lower-extremityischemic ulceration, or amputation with either ankle brachial index ≤0.9or other diagnostic testing (e.g., angiogram, toe-brachial index, orimaging study),

wherein the method comprises administering to the subjects atherapeutically effective amount of pemafibrate or a pharmaceuticallyacceptable salt thereof.

The sixth embodiment, the invention provides a method of prolonging thetime to first occurrence of:

a) any component of the 3-component composite endpoint of non-fatal MI,non-fatal stroke, or cardiovascular death;

b) any component of the primary endpoint or hospitalization for heartfailure;

c) any component of the primary endpoint or all-cause mortality;

d) any component of the primary endpoint, any coronaryrevascularization, or hospitalization for heart failure; or

e) any new or worsening peripheral artery disease, defined as incidenceof lower extremity revascularization, intermittent claudication, restpain, lower extremity ischemic ulceration, or major amputation witheither ankle-brachial index ≤0.9 or other diagnostic testing (eg,toe-brachial index, angiogram, or other imaging study).

Pemafibrate achieves these benefits without any significant safetyconcerns, even when co-administered with a statin.

The dosing of the pemafibrate is preferably defined based on route ofadministration, dose, and length of treatment. The preferred route ofadministration is oral. Pemafibrate can be administered to a patient inthe fed or fasting state.

The therapeutically effective amount of pemafibrate can be defined as arange of suitable doses on a daily basis. Thus, in one embodiment thetherapeutically effective amount is from 0.1 to 1.0 mg of pemafibrate ora pharmaceutically acceptable salt thereof, administered orally per day.In another embodiment the therapeutically effective amount is from 0.2to 0.8 mg of pemafibrate or a pharmaceutically acceptable salt thereof,administered orally per day. In still another embodiment thetherapeutically effective amount is 0.4 mg of pemafibrate or apharmaceutically acceptable salt thereof, administered orally per day.These doses are preferably based on the weight of the free base ofpemafibrate.

The dose of pemafibrate can be administered as one dose per day or intwo, three or four evenly divided doses per day.

In some embodiment, pemafibrate can be administered for atherapeutically effective period of time. The therapeutically effectiveperiod of time refers to the period of time necessary to prevent theoccurrence of cardiovascular events, and varies depending on theconditions of a patient being treated, extent and severity of riskfactors, and other factors such as the patient's age. Thetherapeutically effective period of time generally equates to three ormore months of treatment, six or more months, one or more years, two ormore years, three or more years, or four or more years.

In some embodiments, lipid values and these risk factors can be combinedin any manner to define patient populations treatable by the methods ofthe present invention, and that any of the cutoff value provided for aparticular parameter can be applied to define the patient. Thus, in oneembodiment, the patient can have high TG and/or low HDL-C. In anotherembodiment, the patient can have high TG and/or low HDL-C, and one ormore selected from the group consisting of controlled LDL-C,atherosclerosis, age (male ≥50 or female ≥55), type 2 diabetes mellitus,elevated non-HDL-C, elevated Apo CIII, elevated remnant cholesterol andatherosclerosis.

Additional advantages of the invention are set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

Other embodiments of the invention may be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

EXAMPLES

In the following examples, efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.) but someerrors and deviations should be accounted for. The following examplesare put forth so as to provide those of ordinary skill in the art with acomplete disclosure and description of how the methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention.

Example 1 Treatment of Dyslipidemia with Pemafibrate as Add-On to StatinTherapy

A placebo-controlled, randomized, double-blind parallel-group study wasperformed to evaluate the treatment effect of pemafibrate indyslipidemia patients on concurrent statin therapy. Dyslipidemiapatients on a stable dose of statin therapy (atorvastatin, rosuvastatinor simvastatin) were randomized to one (1) of seven (7) treatmentgroups: once daily [QD] pemafibrate 0.1 mg, 0.2 mg, or 0.4 mg; twicedaily [BID] pemafibrate 0.05 mg, 0.1 mg, or 0.2 mg; or placebo, for 12weeks of pemafibrate treatment, and were followed for an additional 2weeks thereafter.

Patients were required to have statin controlled LDL-C (≤10 mg/dl abovethe NCEP ATP III target) or on a maximum tolerated dose of statin, butresidual dyslipidemia (TG ≥175 and ≤500 mg/dl; HDL-C ≤50 mg/dl for maleand ≤55 mg/dl for female). Differences in changes of TG, non-HDL-C, ApoCIII, and remnant-C between treatment groups were evaluated forsignificance. Overall, 408 patients were randomized to treatment, and375 patients (91.9%) completed the study. There were no significantdifferences between the 7 treatment groups at baseline. 99% of patientswere white Caucasian, 31.9% had a history of coronary heart disease,37.8% had type 2 diabetes mellitus; intensity of statin treatment washigh in 46.3% of patients, moderate in 48.1%. The results of the studyare depicted in FIGS. 1A-1D.

The following observations also were made:

-   -   Pemafibrate significantly reduced TG levels in all treatment        groups after 12 weeks (FIG. 1A).    -   Non-HDL-C levels were significantly reduced at 0.2 mg BID and        0.2 mg QD doses (FIG. 1B).    -   LDL-C levels were significantly increased at 0.1 mg BID (22.46%        vs. placebo), 0.2 mg BID (24.25%), and 0.4 mg QD (18.74%), with        no significant change in total Apo B at any dose.    -   Significant increases in HDL-C (7.35% to 10.95% vs. placebo)        were observed at all doses except the 0.1 mg QD dose.    -   There were dose-dependent reductions with BID dosing for TG,        non-HDL-C, Apo CIII (FIG. 1C), remnant-C (FIG. 1D), and Apo B48        (−40.8% to −63.4%) that reached statistical significance for        both TG and non-HDL-C at 0.2 mg BID; the effects of QD dosing        were more variable across doses.    -   Adverse events occurred in 56.7% of patients on placebo vs.        46.4% of those on pemafibrate, with no relationship to dose. No        other safety concerns were observed.

Example 2 Retrospective Analysis of Type 2 Diabetes Patients

A post-hoc analysis of patients with type 2 diabetes mellitus (HbA1c≤10%) who participated in the study described in Example 1, wasundertaken to determine the treatment effect of pemafibrate in diabetespatients. Overall, 161 type 2 diabetes mellitus patients were randomizedand 154 patients completed treatment. 99.4% were white Caucasian, and35.7% had a history of CHD; intensity of statin therapy was high in45.5% of patients, moderate in 49.4%. The results of the analysis arereported in FIGS. 2A-2D.

Tables 1-4 also report the results of the analyses, and compare theresults to the results obtained for the general residual dyslipidemiapopulation studied in Example 1.

TABLE 1 (TG Reduction Relative to Placebo) Residual Diabetic DoseDyslipidemia Population Sub-Population 0.05 mg BID −36.1 −47.0  0.1 mgBID −45.8 −67.4  0.2 mg BID −54.4 −56.1  0.1 mg QD −34.0 −44.7  0.2 mgQD −37.7 −48.1  0.4 mg QD −42.7 −47.9

TABLE 2 (Non HDL-C Reduction Relative to Placebo) Residual Diabetic DoseDyslipidemia Population Sub-Population 0.05 mg BID −6.8 −14.2  0.1 mgBID −7.4 −17.3  0.2 mg BID −8.9 −10.9  0.1 mg QD −5.2 −5.5  0.2 mg QD−9.1 −15.3  0.4 mg QD −7.8 −10.3

TABLE 3 (Apo CIII Reduction Relative to Placebo) Residual Diabetic DoseDyslipidemia Population Sub-Population 0.05 mg BID −15.5 −26.1  0.1 mgBID −28.7 −37.3  0.2 mg BID −36.0 −39.7  0.1 mg QD −17.1 −23.8  0.2 mgQD −24.3 −35.4  0.4 mg QD −23.8 −32.4

TABLE 4 (Remnant-C Reduction Relative to Placebo) Residual Diabetic DoseDyslipidemia Population Sub-Population 0.05 mg BID −35.6 −55.6  0.1 mgBID −48.8 −81.8  0.2 mg BID −58.0 −70.7  0.1 mg QD −39.9 −62.1  0.2 mgQD −45.9 −66.3  0.4 mg QD −45.5 −58.7

As can be seen, pemafibrate consistently reduced TG, non-HDL-C, ApoCIII, and remnant cholesterol values more in type 2 diabetes patientsthan in the general dyslipidemia population treated in Example 1.

The following observations also were made:

-   -   Pemafibrate significantly reduced TG levels across all doses        (FIG. 2A).    -   Decreases in non-HDL-C were less consistent across treatment        groups (FIG. 2B); pemafibrate significantly increased BQ LDL-C        at 0.2 mg BID (1.8%) and 0.1 mg QD (6.7%), with no significant        change in total Apo B at any dose.    -   Pemafibrate significantly reduced Apo CIII (FIG. 2C), remnant-C        (FIG. 2D), and Apo B48 levels at all doses.    -   Significant increases were seen for HDL-C at doses of 0.05 mg        BID (11.39%), 0.1 mg BID (11.94%), and 0.2 mg QD (9.48%).    -   With the exception of Apo CIII and BQ LDL-C levels, changes in        lipid parameters were not further increased at doses higher than        0.1 mg BID.    -   57.7% of placebo patients reported an adverse event compared        with 25.0% to 71.4% of pemafibrate-treated patients, with no        relationship to dose.

Example 3 Effectiveness of Pemafibrate as Add-On to Pitavastatin Therapy

A double-blind parallel-group study was undertaken to determine theeffectiveness of pemafibrate when added to an existing statin regimen. Atotal of 188 patients with fasting high TG (≥200, <1000 mg/dL) andnon-HDL-C (≥150 mg/dL), treated with pitavastatin (once daily, 2 mg/day)were randomized to 12-week treatment groups; placebo (n=46), twice-dailypemafibrate 0.1 (n=45), 0.2 (n=49) and 0.4 mg/day (n=48). The primaryendpoint was the percentage change in TG from baseline and incidence ofadverse drug reactions (ADRs) and adverse events (AEs).

The results of the study are reported in FIGS. 3A-3D and summarized asfollows. Fasting TG reduction was as follows; placebo: −6.9%,pemafibrate 0.1, 0.2 and 0.4 mg: −46.1%, −53.4% and −52.0%. Allpemafibrate groups had significant reductions compared with placebo(P<0.001). Fasting non-HDL-C reductions were −5.9% with placebo and−11.3, −14.1 and −13.3% with pemafibrate 0.1, 0.2 and 0.4 mg,respectively. Significant increase in HDL-C, and reductions in VLDL-C,remnant lipoprotein cholesterol and Apo CIII compared to placebo werefound in all pemafibrate groups (P<0.01). Although pemafibrate had aneutral effect on total LDL-C, HPLC analysis revealed a significantreduction of very small LDL-C with pemafibrate compared to the placebogroup (P<0.05). Moreover, the highest dose of pemafibrate (0.4 mg/day)showed significant reductions in fasting plasma glucose and HOMA-IRcompared to placebo (P=0.003 and 0.019, respectively).

REFERENCES CITED

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. Thereferences disclosed are also individually and specifically incorporatedby reference herein for the material contained in them that is discussedin the sentence in which the reference is relied upon.

-   The FIELD study investigators. Effects of long-term fenofibrate    therapy on cardiovascular events in 9795 people with type 2 diabetes    mellitus (the FIELD study): randomised controlled trial, LANCET    2005; 366:1849-1861.-   The ACCORD Study Group. Effects of Combination Lipid Therapy in Type    2 Diabetes Mellitus, N ENGL J MED 2010; 362:1563-1574.-   Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F,    Turner R C: Homeostasis model assessment: insulin resistance and    beta-cell function from fasting plasma glucose and insulin    concentrations in man. DIABETOLOGIA 1985; 28:412-419.-   Ishibashi S, Arai H, Yamashita S, Araki E, Yamada N, Beneficial    effects of K-877, a highly potent and selective PPARα agonist, on    plasma lipoprotein profile in patients with atherogenic dyslipidemia    (80^(th) European Atherosclerosis Society (EAS) Congress 2012;    M4.5).-   Araki E, Ishibashi S, Yamashita S, Arai H, Yokote K, Suganami H and    Kodama T: A highly potent and specific PPAR alpha agonist, K-877,    improves lipid profiles and insulin sensitivity in dyslipidemia    patient; an integrated analysis of 3 phase 2/3 trials (50^(th)    European Association for the Study of Diabetes (EASD) 2014; 663).

The invention claimed is:
 1. A method of preventing the occurrence of cardiovascular events in a patient with one or more risk factors, wherein the patient is on concomitant lipid-lowering therapy other than concomitant moderate to high intensity statin therapy and has an LDL-C concentration ≤70 mg/dL, comprising administering to the patient a therapeutically effective amount of pemafibrate or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein the patient has type 2 diabetes mellitus.
 3. The method of claim 1, wherein the patient has an age greater than or equal to 50 years if male or 55 years if female, or systemic atherosclerosis.
 4. The method of claim 1, wherein the patient is taking concurrent statins.
 5. The method of claim 1, wherein the patient has a fasting TG concentration ≥200 mg/dL and <500 mg/dL.
 6. The method of claim 1, wherein the patient has an HDL-C concentration ≤40 mg/dL.
 7. The method of claim 1, wherein the patient has: a) type 2 diabetes mellitus; b) a fasting TG concentration ≥200 mg/dL and <500 mg/dL; and c) an HDL-C concentration ≤40 mg/dL.
 8. The method of claim 1, wherein the patient is taking concurrent statins and has: a) type 2 diabetes mellitus; b) a fasting TG concentration ≥200 mg/dL and <500 mg/dL; and c) an HDL-C concentration ≤40 mg/dL.
 9. The method of claim 7 wherein: a) the patient has an age greater than or equal to 50 years if male or 55 years if female, or systemic atherosclerosis; b) the therapeutically effective amount of pemafibrate or pharmaceutically acceptable salt thereof is 0.4 mg, administered orally per day; and c) the cardiovascular events are selected from nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina requiring unplanned coronary revascularization, cardiovascular death, and combinations thereof.
 10. The method of claim 1, wherein the therapeutically effective amount of pemafibrate or pharmaceutically acceptable salt thereof is 0.4 mg, administered orally per day.
 11. The method of claim 1, wherein the therapeutically effective amount of pemafibrate or a pharmaceutically acceptable salt thereof is 0.2 mg, administered orally twice daily.
 12. The method of claim 1, wherein the cardiovascular events are selected from nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina requiring unplanned coronary revascularization, cardiovascular death, and combinations thereof.
 13. The method of claim 1, wherein the patient has type 2 diabetes mellitus as defined by: a) a hemoglobin A1c level of 6.5% or greater; and b) a plasma glucose level: i) greater than or equal to 126 mg/dL when fasting; ii) greater than or equal to 200 mg/dL at 2 hours during oral glucose tolerance testing; or iii) greater than or equal to 200 mg/dL with classic type 2 diabetes mellitus symptoms.
 14. The method of claim 1, wherein the patient has cardiovascular disease.
 15. A method of preventing the occurrence of cardiovascular events in a patient with one or more risk factors, wherein the patient has an LDL-C concentration ≤70 mg/dL, comprising administering to the patient a therapeutically effective amount of pemafibrate or a pharmaceutically acceptable salt thereof.
 16. The method of claim 15, wherein the patient is taking concurrent statins.
 17. The method of claim 15, wherein the patient has a fasting TG concentration ≥200 mg/dL and <500 mg/dL.
 18. The method of claim 15, wherein the patient is a man with an HDL-C concentration >35 mg/dL and ≤40 mg/dL.
 19. The method of claim 15 wherein the patient has: a) type 2 diabetes mellitus; b) a fasting TG concentration ≥200 mg/dL and <500 mg/dL; and c) an HDL-C concentration ≤40 mg/dL. 